Is there a protective role of testosterone against high-grade prostate cancer?

Historically, testosterone has almost been a synonym for prostate cancer, and therefore many men have been - and still are - denied testosterone therapy, despite having testosterone deficiency.1

A rapidly growing number of studies have challenged the long-standing belief about a putative detrimental association between testosterone and prostate cancer development and/or progression.2-5 Here we present the results of a study published in The Aging Male, which investigated the incidence and severity of prostate cancer in testosterone treated versus non-testosterone treated patients who underwent prostate biopsy.1

Key Points

Testosterone deficient men who receive testosterone therapy have a lower incidence of prostate cancer.

Testosterone therapy may protect against high-grade prostate cancer.

Both the development and progression of prostate cancer is lower in men who receive testosterone therapy, compared to untreated men.

What is known

A pervasive concern with testosterone therapy is prostate disease.1,6 The fear that higher testosterone level will increase prostate cancer growth originated from a theory of testosterone-dependent prostate cancer growth that was seen in castrated men.6 This finding is not relevant to testosterone therapy in hypogonadal (testosterone deficient) men; even low testosterone levels that are seen in men with testosterone deficiency are typically above the androgen saturation point (i.e. the level above which further increases in testosterone levels will not affect the prostate because it has already become saturated with androgens).7

Contrary to widespread belief, studies show that long-term testosterone therapy for up to 17 years does not increase prostate cancer incidence.8 When prostate cancer does develop, it is men with low testosterone levels who develop higher grade (more advanced) prostate cancer.9-13 In fact, data suggest that low testosterone levels, especially low free testosterone, may be a marker for more aggressive prostate cancer.14-16 More recently, a study showed that low testosterone level is an independent risk factor for high-grade prostate cancer.17

A meta-analysis of 43 studies showed that testosterone therapy for hypogonadism does not increase prostate cancer risk or Gleason grade of cancer detected in testosterone treated vs untreated men.18 Another meta-analysis of 22 studies concluded that testosterone therapy does not promote prostate cancer development or progression.19

What this study adds

In the present study, the incidence and severity of prostate cancer, Gleason scores and tumor staging were assessed in prostate biopsies from hypogonadal men undergoing testosterone therapy, and compared with biopsies from eugonadal men and untreated hypogonadal men.1

The study was conducted between 2008 and 2013 and included 553 patients. Mean age at biopsy was 61 (range 46–81 years) and PSA 3.7 (range 0.28–7.23 mg/mL). The incidence and severity of prostate cancer was assessed via biopsy in three patient groups presenting at a urology clinic:

(a) 42 testosterone deficient men.

(b) 162 untreated testosterone deficient men.

(c) 349 non-testosterone deficient men.

As illustrated in table 1, pathological analysis of prostate biopsies examining the incidence and severity of prostate cancer revealed that:

17% (7 patients) of treated hypogonadal men had a positive biopsy, a Gleason score of ≤6 in 71% and >6 in 29% of men, a predominant score of 3 in all men (100%) and tumour staging of II in 86% men;

52% (84 patients) of untreated hypogonadal men had a positive biopsy, a Gleason score of ≤6 in 41% and >6 in 60% men, a predominant score of 3 (77%) and tumour staging of II (42%) or III (41%);

38% (132 patients) of eugonadal men had a positive biopsy, a Gleason score of ≤6 in 42% and >6 in 58% of men, a predominant score of 3 (83%) and tumour staging of II (45%) or III (48%).

It was concluded that the incidence of prostate cancer was lowest in hypogonadal men receiving testosterone therapy, with significantly lower severity of prostate cancer in terms of staging and grading in the testosterone treated hypogonadal men.1 These results suggest that testosterone therapy might have a protective effect against high-grade prostate cancer.1

Commentary

This study shows for the first time that testosterone therapy may protect against both development and progression of prostate cancer in testosterone deficient men.1 A few days after the publication of this study another study was published, which demonstrated that testosterone therapy for >1 year has been associated with a 56% reduced risk of aggressive prostate cancer.20

A well-established treatment of prostate cancer is androgen deprivation therapy, which reduces testosterone levels to castrate levels.21 This has contributed to the belief that since depriving the prostate of testosterone (androgens) reduces growth of prostate cancer, then high levels of testosterone must be bad for the prostate.6 However, this reasoning is based on “guilt by association” 6 and fails to acknowledge results from more recent studies, which have given rise to the saturation model 7 and the dynamic model.22

The dynamic model of the role of testosterone in prostate cancer development postulates that the absolute value of testosterone measured at a single time point is not indicative of prostate cancer risk.22 Instead, the key factor is the magnitude of the age-related decline in testosterone, from its highest peak in young adulthood to the hypogonadal level where symptoms and signs of testosterone deficiency appear.22 The risk of prostate cancer increases when testosterone levels fall below a hypogonadal testosterone threshold, which varies between individuals. As testosterone level falls below this threshold, previously healthy prostate cells, now being deprived of testosterone, turn into prostate cancer cells.22

The purpose of testosterone treatment is to compensate for the age-related declines in testosterone and to maintain testosterone levels above the threshold, below which the prostate carcinogenesis process is triggered.22 This explains why the untreated hypogonadal men in the study reported ended up with a higher prostate cancer incidence overall, as well as more aggressive prostate cancer than hypogonadal men who received testosterone therapy.1 The higher incidence of prostate cancer and aggressiveness in eugonadal men compared to testosterone treated men could have occurred because testosterone treatment in the hypogonadal men achieved higher testosterone levels than those seen in eugonadal men, who despite being classified as eugonadal may have had suboptimal testosterone levels.

The dynamic model of the role of testosterone in prostate cancer development also explains why other testosterone treatment studies found no higher risk of prostate cancer than that seen in the general population.23-25 Notably, a study published in the Lancet showed that the risk of prostate cancer diagnosis was decreased by 40% in men with the longest duration of testosterone treatment (25-51 months). 26 The demonstrated lack of change in prostate histology after testosterone therapy confirms its safety.25

While it is well accepted that testosterone therapy is contraindicated in metastatic prostate cancer, the historical fear that testosterone is bad for the prostate has clearly been refuted. As evidenced in this study 1 and explained by the dynamic model of the role of testosterone in prostate cancer development 22, denying or delaying testosterone treatment can actually put men at a significantly increased risk of prostate cancer.